Leading Toxoplasma expert Michael White looks for ways to shut down the malaria-related parasites [multimedia]

The neglected parasitic infection that USF Health microbiologist Michael White, PhD, has spent the last 20 years studying causes few, if any, symptoms in healthy people. But the disease caused by the malaria-related parasite T. gondii, known as toxoplasmosis, can cause life-threatening illness in people with weakened immune systems, such as those with HIV/AIDS, the elderly and babies born to women infected during pregnancy.

“Toxoplasma can be a dangerous infection that’s easy to overlook, because it’s not filling our emergency rooms,” said Dr. White a professor of molecular medicine and global health and one of the world’s leading experts on the malaria-related parasite. “But it’s a potential time bomb.”

Michael White, PhD, is one of the world’s leading experts on the malaria-related parasites T. gondii.

Listen to Dr. White talk about how the process of science is like a puzzle.

People can acquire toxoplasmosis several ways — usually by direct exposure to the feces of cats or by eating undercooked meat of an infected animal, or drinking water contaminated with the organism. Up to 15 percent of the world’s population is estimated to be infected with T. gondii, and in some parts of the world where sanitation is poor and eating raw or undercooked meat is customary, nearly all people carry the parasite, Dr. White said. In Brazil, particularly virulent strains of the parasite cause a high-incidence of vision-threatening eye disease.

Dr. White is deputy director of the Florida Center of Excellence in Drug Discovery and Innovation at USF. His research team combines genetic, biochemical and cell biology approaches to understand how the parasite replicates, establishes chronic infection and interacts with host cells. Their goal is to find new ways to combat the pervasive parasite, which has both rapidly dividing acute stage destructive to healthy tissue and a chronic stage where egg-like cysts remain invisible to the immune system, basically hiding out in brain or muscle tissues to avoid attack.

No drugs or vaccines currently exist to treat or prevent the chronic, or dormant, stage of the disease.

Dr. White with his research team at the USF-based Florida Center of Excellence in Drug Discovery and Innovation. From left: Jeanine Yacoub, graduate student in the Department of Chemistry; Dong-Pyo Hong, PhD, assistant professor; Elena Suvorova, PhD; assistant professor; Carmelo Alvarez, MS, research technician; and Anatoli Naumov, PhD, assistant professor.

“A major clinical challenge with toxoplasmosis is that the T. gondii cysts can quietly slip into into your brain or muscle cells, where they can settle without growing” until weakened immunity reactivates the disease, Dr. White said. “The drugs used to treat toxoplasma infections only attack growth, so they do not cure the lifelong infection. They help reduce the danger of acute infection for AIDS patients or others with compromised immune systems.”

In the past several years Dr. White’s laboratory, working with partners at the University of Georgia, made several intriguing discoveries about the growth and development of the malaria-related parasite. Their work with T. gondii may also lead to new therapies to combat drug-resistant strains of malaria, a mosquito-borne tropical disease threatening to resurge as a public health crisis in certain parts of the world.

To understand the Toxoplasma research, it helps to know that ages ago the ancestors of malaria parasites genetically merged with an ancestor of plants, and the primitive plant donated proteins known as AP2 factors to the future malaria family. Also, unlike plant and animal species – where chromosomes get one shot at replication or else the cell dies or turns into cancer – these malaria-related parasites manage to multiply exponentially while avoiding cell death.

Dr. White, with colleague Dr. Elena Suvorova, conducts NIH-funded research investigating molecular mechanisms underlying the growth and development of T. gondii with the aim of eradicating the pervasive malaria-related parasite.

In a 2013 study appearing in the Proceedings of the National Academy of Sciences, Dr. White’s team demonstrated that AP2 factors are instrumental in flipping a developmental “switch” that transitions T. gondii from its acute to dormant stage. The USF study showed that, like the AP2 factors that help a plant survive in stressful environments including poor water or soil conditions, the AP2 factors of T gondii help regulate when the time is right to grow or when to form tissue cysts that may lie dormant in people for many years before the host immune system detects their presence.

Dr. White and colleagues were also the first to uncover part of the mysterious process by which T. gondii spreads at explosive and potentially deadly rates inside humans and other animals. In a study published this spring in the high-impact journal PLOS Biology, the researchers discovered how these ancient parasites pull off replicating their chromosomes hundreds or even thousands of times before spinning off into daughter cells with perfect similitude.

The explanation: Toxoplasma parasites have a modified “control room,” called the centrosome, which imposes order on the replication chaos, Dr. White said. “Unlike the comparatively simple centrosome present in human cells, the parasite ‘control room’ has two distinct operating machines: one machine controls chromosome copying, while the other machine regulates when to form daughter cell bodies. Working together, but with independent responsibilities, parasite centrosome machines can dictate the scale and timing of pathogen replication.”

Exposure by cleaning the litter box of an infected cat is one way in which the Toxoplasma parasite can be transmitted to humans. The tiny organism is transmitted to cats by rodents, and the parasite thrives in the cat’s gut, producing countless egg-like cells that are passed along in the feces.

Dr. White’s team found that the operation of the centrosome requires kinases, the same enzymes most effectively attacked by certain cancer drugs. So far, they’ve identified within both centrosome machines six kinases that could be potential drug targets.

This new knowledge and the groundbreaking understanding of the centrosome’s function suggests that the system’s highly-efficient cell proliferation can be disrupted to kill the malaria-related parasites.

“These stealthy parasites evolved a more complex mechanism to control cell division, because they wanted to avoid the immune system — but they created a vulnerability in doing that,” Dr. White said. “They are like Humpty Dumpty. When we hit one of the kinases, the parasite breaks apart and can’t be put back together… And if we can develop drugs to inhibit two or more of these critical kinases, then we could potentially overcome the problem of drug-resistant strains.”

The researchers have already begun screening small molecules to identify the best potential inhibitors of the centrosome kinases they’ve identified.

Dr. White in the High Throughput Screening Core at CDDI, where USF researchers screen small molecules to help identify the best inhibitors of the T. gondii centrosome kinases (potential drug targets) they’ve identified.

Dr. White’s laboratory has also discovered proteins that control expression of the chronic, or dormant, phase of toxoplasmosis. In animal model experiments, the researchers were able to alter parasite genes active in the acute phase of the disease to eliminate the “silent” stage of the disease, perhaps by “teaching” the immune system to combat the dormant stage, Dr. White said.

The work may lead to a vaccination to prevent the chronic stage of the disease in animals, which is one of the sources of infection for humans, he added. “If we could eradicate the toxoplasma from poultry, pigs and other livestock, we could help break the cycle of transmission from the food supply (to humans).”

Dr. White joined USF in 2009 from Montana State University where he was a professor of veterinary molecular biology. He received his PhD in microbiology from Oregon University in 1983, and completed a postdoctoral research fellowship at the University of Washington focusing on how to attack the growth of cancer cells. In the early 1990s, under the mentorship of electron microscopist C.A. Speer at Montana State, his research emphasis shifted to eukaryotic pathogens, parasites that can lead to a variety of diseases in humans, animals and plants.

Since 1996, he has investigated molecular mechanisms underlying the growth and development of T gondii with the aim of eradicating the malaria-related parasite using a two-pronged approach: reducing its proliferative capacity and breaking the cycle of transmission between animal and human. Across his career, Dr. White’s research has been continuously funded by grants from the U.S. Department of Agriculture and, since 1988, by grants from the National Institutes of Health. He is the principal investigator for two active NIH R01 grants totaling more than $4.8 million, with a third $2.6-million grant pending.

Image of Toxoplasma gondii parasites dividing provided by Ke Hu and John Murray (DOI: 10.1371/journal.ppat.0020020.g001). Dr. White and colleagues were the first to uncover part of the mysterious process by which T. gondii spreads at explosive and potentially deadly rates inside humans and other animals.

Dr. White chairs the NIH Pathogenic Eukaryotes Study Section and is a member of the Genome Consortium for Toxoplasma gondii. He serves as an ad-hoc reviewer for several journals, including PLoS Pathogens, Molecular Microbiology, and Eukaryotic Cell.

His laboratory, based in the USF Research Park, collaborates with USF medicinal chemist Jim Leahy, PhD, and he supports postdoctoral fellows at the University of Georgia and Indiana University School of Medicine.

Something you might not know about Dr. White: As a teen growing up in Albuquerque, New Mexico, he raised Blue Dutch rabbits. He also collected rattlesnakes, tarantulas and blue racers from the mesa bordering his home. “It was the only field biology I ever did,” he said.